Estrogen receptor (ER) is an important transcription factor which plays a key role in reproductive, cardiovascular and central nervous systems and bone tissue. In female body, there are more than 400 tissues or organs containing ER, including for example uterus, vagina, breast, pelvic cavity (anadesma and connective tissues), skin, urocyst, urethra, ossature and brain. During the menopause, the secretion of estrogens is dramatically decreased, and the tissues, organs and systems related to estrogen change accordingly. Subsequently, elderly women develop commonly climacteric symptoms including hot flashes, sweating, insomnia, depression, headache, vaginal dryness, cardiovascular symptoms, urinary incontinence, swelling feeling, breast tenderness and fatigue (Payer, L: The menopause in various cultures. In: A portrait of the menopause. Expert reports on medical and therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, N.J., USA, 1991. pp 3-22; and Rekers H: Mastering the menopause. In: A portrait of the menopause. Expert reports on medical and therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, N.J., USA, 1991. pp 23-43). Long-term estrogen deficiency would also induce osteoporosis, senile dementia and cardiovascular disorders.
Estrogen replacement therapy is increasingly used for the treatment of climacteric symptoms in women. Estrogen replacement therapy is also shown to be beneficial in decreasing the risk of osteoporotic bone fractures, preventing Alzheimer's disease (Henderson V W: Estrogen, cognition, and as woman's risk of Alzheimer's disease. Am J Med 103 (3A): 11S-18S, 1997) and lowering LDL-cholesterol values and thus preventing cardiovascular diseases (Grodstein F, Stampfer, M J: Estrogen for women at varying risk of coronary disease. Maturitas 30: 19-26, 1998). However, use of estrogen replacement therapy increases the risk of uterine and breast cancers (Lobo R A: Benefits and risks of estrogen replacement therapy. Am J Obstet Gynecol 173:982-990, 1995).
Selective estrogen receptor modulators (SERMs) show different activities to ER in different tissues. They mimic estrogen in some tissues and have anti-estrogen activity in others. It would be most desirable to develop tissue-specific estrogens, which could be ER agonists in bone tissue, cardiovascular system and central nervous system, while being ER antagonists in tissues like breast and uterus, and without estrogenic adverse effects.
As the first SERMs drug approved for the treatment of osteoporosis, Raloxifene exhibits ER antagonism in breast and uterus and ER agonism in bone tissue and cardiovascular system. However, Raloxifene has no advantage over Tamoxifen in terms of therapeutic effect on breast cancer, while it has adverse effects such as hot flashes, leg cramps, headache and weight gain (Davies G C, et al., Obstet Gynecol 193: 558-565(1999)).
Obviously, it would be desirable to develop more potent and safer drugs in preventing and treating estrogen-dependent diseases and conditions.